Blood glucose level control

ABSTRACT

A pancreatic controller ( 102 ), comprising: a glucose sensor ( 118 ), for sensing a level of glucose or insulin in a body serum; at least one electrode ( 110, 112 ), for electrifying an insulin producing cell or group of cells; a power source ( 104 ) for electrifying said electrode with a pulse that does not initiate an action potential in said cell and has an effect of increasing insulin secretion; and a controller ( 106 ) which receives the sensed level and controls said power source to electrify said electrode to have a desired effect on said level.

RELATED APPLICATIONS

This application is a U.S. national phase filing of PCT application No.PCT/IL00/00132, filed Mar. 5, 2000. This application claims the benefitunder 119(e) of U.S. provisional application 60/123,532, filed Mar. 5,1999, the disclosure of which is incorporated herein by reference. Thisapplication is a continuation-in-part of U.S. application Ser. No.09/481,253, filed Jan. 11, 2000, now U.S. Pat. No. 6,571,127, which is acontinuation of PCT/IL97/00243, filed Jul. 16, 1997.

FIELD OF THE INVENTION

The present invention is related to the field of controlling blood serumglucose levels, especially by application of electric fields to apancreas, to control insulin output.

BACKGROUND OF THE INVENTION

Control of insulin secretion is very important, as there are many livingdiabetes patients whose pancreas is not operating correctly. In sometype of diabetes, the total level of insulin is reduced below thatrequired to maintain normal blood glucose levels. In others, therequired insulin is generated, but only at an unacceptable delay afterthe increase in blood glucose levels. In others, the body is, for somereason, resistant to the effects of insulin.

Although continuous (e.g., avoiding dangerous spikes and dips) of bloodglucose level is desirable, it cannot currently be achieved in somepatients.

The insulin secretion process operates as follows: glucose levels in theblood are coupled to depolarization rates of beta islet cells in thePancreas. It is postulated that when there is a higher glucose level, ahigher ratio of ATP/ADP is available in the beta cell and this closespotassium channels, causing a depolarization of the beta cell. When abeta cell depolarizes, the level of calcium in the cell goes up and thiselevated calcium level causes the conversion of pro-insulin to insulinand causes secretion of insulin from the cell.

The beta cells are arranged in islets, within a reasonable range ofblood glucose levels, an action potential is propagated in the islet.Generally, the electrical activity of a beta cell in an islet is in theform of bursts, each burst comprises a large number of small actionpotentials.

In PCT publication WO 99/03533, the disclosure of which is incorporatedhere by reference, it was suggested to reduce the output of a pancreasusing a non-excitatory electric field.

PCT publication WO 98/57701 to Medtronic, the disclosure of which isincorporated herein by reference, suggests providing a stimulatingelectric pulse to an islet, causing an early initiation of a burst andthus, increasing the frequency of the bursts and increasing insulinsecretion.

The above PCT publication to Medtronic suggests providing a stimulating(e.g., above stimulation threshold) pulse during a burst, therebystopping the burst and reducing insulin secretion. This publication alsosuggests stimulating different parts of the pancreas in sequence,thereby allowing unstimulated parts to rest.

However, one limitation of the methods described in the Medtronic PCTpublication is that increasing the burst frequency increases the levelof intra-cellular calcium in the beta cells over a long period of time,without the level being allowed to go down, during intra-burstintervals. This increase may cause various cell death mechanisms to beactivated and/or otherwise upset the normal balance of the beta cell,eventually killing the cell. In addition, such high calcium levels maycause hyper-polarization of beta cells, thereby reducing insulinsecretion and preventing propagation of action potentials. To date, noworking electrical pancreatic control device is known.

SUMMARY OF THE INVENTION

An aspect of one preferred embodiment of the invention relates to amethod of increasing insulin secretion, while avoiding unacceptablecalcium level profiles. In a preferred embodiment of the invention,insulin output is increased by extending a burst duration, whilemaintaining a suitably lengthy interval between bursts, thus allowingcalcium levels to decay during the interval. Alternatively oradditionally, insulin output is increased by increasing theeffectiveness of calcium inflow during a burst, possibly withoutchanging the burst frequency and/or duty cycle. Alternatively, in bothmethods, the burst frequency may be reduced and/or the intervalincreased, while allowing higher insulin output levels or maintainingsame output levels.

In a preferred embodiment of the invention, the effects on insulinsecretion are provided by applying a non-excitatory pulse to at leastpart of the pancreas. As used herein the term non-excitatory is used todescribe a pulse that does not generate a new action potential, but maymodify an existing or future potential. This behavior may be a result ofthe pulse, amplitude, frequency or pulse envelope, and generally alsodepends on the timing of the pulse application. It is noted that asingle pulse may have excitatory and non-excitatory parts. For example a100 ms pacing pulse, may cease to have a pacing effect after 20 ms andhave real non-excitatory effects after 40 ms.

The pulse may be synchronized to the local electrical activity, forexample, to bursts or to individual action potentials. Alternatively oradditionally, the pulse may be synchronized to the cycle of changes ininsulin level in the blood (typically a 12 minute cycle in healthyhumans). Alternatively, the pulse may be unsynchronized to local orglobal pancreatic electrical activity. Alternatively, the applied pulsemay cause synchronization of a plurality of islets in the pancreas, forexample by initiating a burst. A two part pulse may be provided, onepart to synchronize and one part to provide the non-excitatory activityof the pulse. Although the term “pulse” is used, it is noted that theapplied electric field may have a duration longer than an actionpotential or even longer than a burst.

An aspect of some preferred embodiments of the invention relates toreducing calcium levels in beta islet cells. In a preferred embodimentof the invention, the levels are reduced by providing an oral drug.Alternatively, the levels are reduced by increasing the interval betweenbursts. The intervals may be increased, for example, by suppressingbursts of action potentials, for example using excitatory ornon-excitatory pulses. Alternatively, an electro-physiological drug isprovided for that purpose. For example, Procainamide HCL and Quinidinesulfate are Na channel antagonists, Minoxidil and Pinacidil are Kchannel activators, and Amiloride HCL is an Na channel and epithelialantagonist. Other suitable pharmaceuticals are known in the art, forexample as described in the RBI Handbook of Receptor Classification, andavailable from RBI inc. This reduction in calcium levels may beperformed to reduce the responsiveness of the pancreas to glucose levelsin the blood. Alternatively or additionally, this reduction is used tooffset negative side effects of drugs or other treatment methods and/orto enforce a rest of at least a part of the pancreas. Alternatively oradditionally, this reduction may be offset by increasing theeffectiveness of insulin secretion.

An aspect of some preferred embodiments of the invention relates topacing at least a portion of the pancreas and, at a delay after thepacing, applying a non-excitatory pulse. The non-excitatory pulse may beprovided to enhance or suppress insulin secretion or for other reasons.In a preferred embodiment of the invention, the pacing pulse provides asynchronization so that the non-excitatory pulse reaches a plurality ofcells at substantially a same phase of their action potentials. Afurther pulse, stimulating or non-excitatory may then be provided basedon the expected effect of the non-excitatory pulse on the actionpotential.

An aspect of some preferred embodiments of the invention relates tosimultaneously providing pharmaceuticals and electrical control of apancreas. In a preferred embodiment of the invention, the electricalcontrol counteracts negative effects of the pharmaceuticals.Alternatively or additionally, the pharmaceutical counteracts negativeeffects of the electrical control. Alternatively or additionally, theelectrical control and the pharmaceutical complement each other, forexample, the pharmaceutical affecting the insulin production mechanismsand the electrical control affecting the insulin secretion mechanism.The electrical control and/or the pharmaceutical control may be used tocontrol various facets of the endocrinic pancreatic activity, includingone or more of: glucose level sensing, insulin production, insulinsecretion, cellular regeneration, healing and training mechanisms and/oraction potential propagation. In a preferred embodiment of theinvention, electrical and/or pharmaceutical mechanisms are used toreplace or support pancreatic mechanisms that do not work well, forexample, to replace feedback mechanisms that turn off insulin productionwhen a desired blood glucose level is achieved. The pharmaceuticals thatinteract with the pancreatic controller may be provided for affectingthe pancreas. Alternatively, they may be for other parts of the body,for example for the nervous system or the cardiovascular system.

An aspect of some preferred embodiments of the invention relates toactivating pancreatic cells in various activation profiles, for exampleto achieve training, regeneration, healing and/or optimal utilization.In a preferred embodiment of the invention, such activating can includeone or more of excitatory pulses, non-excitatory pulses and applicationof pharmaceuticals and/or glucose. It is expected that diseased cellscannot cope with normal loads and will degenerate if such loads areapplied. However, by providing sub-normal loads, these cells cancontinue working and possibly heal after a while using self healingmechanisms. In particular, it is expected that certain diseased cells,when stimulated at at least a minimal activation level, will heal,rather than degenerate. Alternatively or additionally, it is expectedthat by stressing cells by a certain amount, compensation mechanisms,such as increase in cell size, response speed and profile to glucoselevels, cell effectiveness and/or cell numbers, will operate, therebycausing an increase in insulin production capability, insulin responsetime and/or other desirable pancreatic parameters. The appropriateactivation profiles may need to be determined on a patient by patientbasis. Possibly, different activation profiles are tested on one part ofthe pancreas, and if they work as desired, are applied to other parts ofthe pancreas. These other parts of the pancreas may be suppressed duringthe testing, to prevent over stressing thereof. Alternatively, they maybe maintained at what is deemed to be a “safe” level of activity, forexample by electrical control or by pharmaceutical or insulin control.

An aspect of some preferred embodiments of the invention relates toelectrically affecting and preferably controlling insulin generation,alternatively or additionally to affecting insulin secretion. In apreferred embodiment of the invention, insulin production is enhanced by“milking” insulin out of beta cells so that their supplies of insulinare always under par. Alternatively or additionally, by under-milkingsuch cells (e.g., prevention of secretion), insulin production isdecreased. In some patients opposite effects may occur—over milking willcause a reduction in insulin production and/or under-milking willincrease insulin production. Alternatively, insulin production issuppressed by preventing a cell from secreting insulin (e.g., bypreventing depolarization), thereby causing large amount of insulin tostay in the cell, and possibly, prevent further production of insulin.Such mechanisms for stopping the production of insulin have beendetected in pancreatic cells.

In a preferred embodiment of the invention, by causing a cell to store alarge amount of insulin, a faster response time can be achieved, whenlarge amounts of insulin are required, for example to combathyperglycemia. The cells can then be systemically depolarized to yieldtheir stores of insulin. Possibly, a plurality of pancreatic cells (thesame or different ones at different times) are periodically set aside toserve as insulin burst providers.

Alternatively or additionally, suppression of insulin output is usedduring medical procedures, to prevent hypoglycemia. Alternatively oradditionally, suppression or enhancement of insulin output is used tooverwork pancreatic tumor cells, so they die from over production orfrom over-storage of insulin. In some cases, the overworking of cellscaused by cycling demand may be used as a form of stress to weakencells, and in combination with another stress source, kill the cells.Alternatively or additionally, suppression of insulin output is used toreduce the activity of an implanted pancreas or pancreatic portion, toassist in its getting over the shock of transplantation.

An aspect of some preferred embodiments of the invention relates tocontrolling the propagation of action potentials and/or other parametersof action potentials in islet cells, alternatively or additionally tocontrolling parameters of burst activity. In a preferred embodiment ofthe invention, a pulse, preferably synchronized to individual actionpotentials in an islet, is used to control the action potential, forexample to increase or decrease its plateau duration. Alternatively oradditionally, a reduction in action potential frequency towards the endof a burst is counteracted, for example by pacing the cells to have adesired frequency or to be more excitable.

In a preferred embodiment of the invention, action potential propagationis controlled, for example enhanced or blocked, by selectivelysensitizing or desensitizing the beta cells in an islet, using chemicaland/or electrical therapy. Enhancement of action potential may be usefulfor increasing insulin production rates, especially if the glucosesending mechanism in some cells are damaged. Suppression of actionpotential propagation is useful for preventing insulin production and/orenforcing rest.

An aspect of some preferred embodiments of the invention relates toindirectly affecting the pancreatic activity by changing pancreaticresponse parameters, such as response time to increases in glucose leveland response gain to increases in glucose level. Thus, for example, anon-responsive pancreas can be sensitized, so that even small changes inglucose level will cause an outflow of insulin. Alternatively, a weak orover-responsive pancreas can be desensitized, so that it isn't requiredto generate (large amounts of) insulin for every small fluctuation inblood glucose level. It is noted that the two treatments can besimultaneously applied to different parts of a single pancreas.

An aspect of some preferred embodiments of the invention relates tosynchronizing the activities of different parts of the pancreas. Suchsynchronization may take the form of all the different parts beingactivated together. Alternatively, the synchronization comprisesactivating one part (or allowing it be become active) while suppressingother parts of the pancreas (or allowing them to remain inactive). In apreferred embodiment of the invention, the synchronization is applied toenforce rest on different parts of the pancreas. Alternatively oradditionally, the synchronization is provided to selectively activatefast-responding parts of the pancreas or slow responding parts of thepancreas.

In a preferred embodiment of the invention, synchronization betweenislets or within islets is enhanced by providing pharmaceuticals, forexample Connexin, to reduce gap resistance. Such pharmaceuticals may beadministered, for example, orally, systemically via the blood locally orlocally, for example via the bile duct. In a preferred embodiment of theinvention, such pharmaceuticals are provided by genetically altering thecells in the pancreas, for example using genetic engineering methods.

An aspect of some preferred embodiments of the invention relates toimplanting electrodes (and/or sensors) in the pancreas. In a preferredembodiment of the invention, the electrodes are provided via the bileduct. Possibly, a controller, attached to the electrode is also providedvia the bile duct. In a preferred embodiment of the invention, theimplantation procedure does not require general anesthesia and isapplied using an endoscope. Alternatively, the electrodes are providedthrough the intestines. Possibly, also the device which controls theelectrification of the electrodes is provided through the intestines. Ina preferred embodiment of the invention, the device remains in theintestines, possibly in a folded out portion of the intestines, whilethe electrodes poke out through the intestines and into the vicinity orthe body of the pancreas. Alternatively, the electrodes may be providedthrough blood vessels, for example the portal vein. In a preferredembodiment of the invention, the electrodes are elongated electrodeswith a plurality of dependent or independent contact points along theelectrodes. The electrodes may be straight or curved. In a preferredembodiment of the invention, the electrodes are poked into the pancreasin a curved manner, for example being guided by the endoscope, so thatthe electrodes cover a desired surface or volume of the pancreas. Theexact coverage may be determined by imaging, or by the detection of theelectric field emitted by the electrodes, during a post implantationcalibration step.

An aspect of some preferred embodiments of the invention relates to apancreatic controller adapted to perform one or more of the abovemethods. In a preferred embodiment of the invention, the controller isimplanted inside the body. An exemplary controller includes one or moreelectrodes, a power source for electrifying the electrodes and controlcircuitry for controlling the electrification. Preferably, a glucose orother sensor is provided for feedback control.

There is thus provided in accordance with a preferred embodiment of theinvention, a pancreatic controller, comprising:

-   -   a glucose sensor, for sensing a level of glucose or insulin in a        body serum;    -   at least one electrode, for electrifying an insulin producing        cell or group of cells;    -   a power source for electrifying said at least one electrode with        a pulse that does not initiate an action potential in said cell        and has an effect of increasing insulin secretion; and    -   a controller which receives the sensed level and controls said        power source to electrify said at least one electrode to have a        desired effect on said level. Preferably, said insulin producing        cell is contiguous with a pancreas and wherein said electrode is        adapted for being placed adjacent said pancreas. Alternatively        or additionally, said controller comprises a casing suitable for        long term implantation inside the body. Alternatively or        additionally, said electrode is adapted for long term contact        with bile fluids. Alternatively or additionally, the apparatus        comprises an electrical activity sensor for sensing electrical        activity of said cell and wherein said power source electrifies        said electrode at a frequency higher than a sensed        depolarization frequency of said cell, thereby causing said cell        to depolarize at the higher frequency.

In a preferred embodiment of the invention, said pulse is designed toextend a plateau duration of an action potential of said cell, therebyallowing more calcium inform into the cell. Preferably, said pulse isdeigned to reduce an action potential frequency of said cell, while notreducing insulin secretion from said cell.

In a preferred embodiment of the invention, said pulse is designed toextend a duration of a burst activity of said cell.

In a preferred embodiment of the invention, said pulse has an amplitudesufficient to recruit non-participating insulin secreting cells of saidgroup of cells.

In a preferred embodiment of the invention, the apparatus comprises atleast a second electrode adjacent for electrifying a second cell ofgroup of insulin secreting cells, wherein said controller electrifiessaid second electrode with a second pulse different from said firstelectrode. Preferably, said second pulse is deigned to suppress insulinsecretion. Preferably, said controller is programmed to electrify saidsecond electrode at a later time to forcefully secrete said insulinwhose secretion is suppressed earlier. Alternatively, said second pulseis designed to hyper-polarize said second cells.

In a preferred embodiment of the invention, said controller electrifiessaid at least one electrode with a pacing pulse having a sufficientamplitude to force a significant portion of said cells to depolarize,thus aligning the cells' action potentials with respect to thenon-excitatory pulse electrification.

In a preferred embodiment of the invention, said controller synchronizesthe electrification of said electrode to a burst activity of said cell.

In a preferred embodiment of the invention, said controller synchronizesthe electrification of said electrode to an individual action potentialof said cell.

In a preferred embodiment of the invention, said controller does notsynchronizes the electrification of said electrode to electricalactivity of said cell.

In a preferred embodiment of the invention, said controller does notapply said pulse at every action potential of said cell.

In a preferred embodiment of the invention, said controller does notapply said pulse at every burst activity of said cell.

In a preferred embodiment of the invention, said pulse has a duration ofless than a single action potential of said cell. Preferably, said pulsehas a duration of less than a plateau duration of said cell.

In a preferred embodiment of the invention, said pulse has a duration oflonger than a single action potential of said cell.

In a preferred embodiment of the invention, said pulse has a duration oflonger than a burst activity duration of said cell.

In a preferred embodiment of the invention, said controller determinessaid electrification in response to a pharmaceutical treatment appliedto the cell. Preferably, said pharmaceutical treatment comprises apancreatic treatment. Alternatively or additionally, said controllerapplies said pulse to counteract adverse effects of said pharmaceuticaltreatment.

In a preferred embodiment of the invention, said controller applies saidpulse to synergistically interact with said pharmaceutical treatment.Alternatively, said controller applies said pulse to counteract adverseeffects of pacing stimulation of said cell.

In a preferred embodiment of the invention, said apparatus comprises analert generator. Preferably, said controller activates said alertgenerator if said glucose level is below a threshold. Alternatively oradditionally, said controller activates said alert generator if saidglucose level is above a threshold.

There is also provided in accordance with a preferred embodiment of theinvention, a method of controlling insulin secretion, comprising:

-   -   providing an electrode to at least a part of a pancreas;    -   applying a non-excitatory pulse to the at least part of a        pancreas, which pulse increases secretion of insulin.        Preferably, the method comprises applying an excitatory pulse in        association with said non-excitatory pulse. Alternatively or        additionally, the method comprises applying a secretion reducing        non-excitatory in association with said non-excitatory pulse.

In a preferred embodiment of the invention, the method comprisesapplying a plurality of pulses in a sequence designed to achieve adesired effect on said at least a part of a pancreas.

BRIEF DESCRIPTION OF THE DRAWINGS

Particular embodiments of the invention will be described with referenceto the following description of preferred embodiments in conjunctionwith the figures, wherein identical structures, elements or parts whichappear in more than one figure are preferably labeled with a same orsimilar number in all the figures in which they appear, in which:

FIG. 1 is a block diagram of a pancreatic controller, in accordance witha preferred embodiment of the invention;

FIG. 2 is a diagram of an exemplary electrical activity of a single betacell, operating at slightly elevated glucose levels;

FIG. 3 is a flowchart of an exemplary control logic scheme, inaccordance with a preferred embodiment of the invention;

FIGS. 4A–4D illustrate different types of electrodes that may besuitable for pancreatic electrification, in accordance with preferredembodiments of the invention;

FIG. 4E illustrates an electrode, in which the body of the controller ofFIG. 1 serves as at least one electrode, in accordance with a preferredembodiment of the invention;

FIG. 5 illustrates a pancreas subdivided into a plurality of controlregions, each region being electrified by a different electrode, inaccordance with a preferred embodiment of the invention;

FIGS. 6A and 6B are flowcharts of implantation methods, in accordancewith preferred embodiments of the invention;

FIG. 7 is a flowchart of an exemplary method of controller implantationand programming, in accordance with a preferred embodiment of theinvention; and

FIG. 8 is a chart showing the effect of electrical stimulation oninsulin levels, in six animals.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

Overview

FIG. 1 is a block diagram of a pancreatic controller 102, in accordancewith a preferred embodiment of the invention. In a preferred embodimentof the invention, device 102 is used to provide controlling pulses ofelectricity to a pancreas 100. Such controlling pulses may includeexcitatory stimulating pulses and non-excitatory pulses. In particular,such pulses can include pacing pulses and action potential modifyingpulses.

In a preferred embodiment of the invention, the controlling pulses areused to control the glucose and insulin level of a patient. Further, aparticular desired profile of glucose and/or insulin may be achieved.Other uses of controller 102 will be evident from the description belowand can include, for example, training, healing and preventing damage ofpancreatic cells.

Exemplary and non-limiting examples of metabolic and/or hormonaldisorders that may be treated by suitable application of the methodsdescribed below, include non-insulin dependent diabetes mellitus,insulin dependent diabetes mellitus and hyperinsulemia.

The following description includes many different pulses that may beapplied to achieve a desired effect, it should be clear that the scopeof the description also covers apparatus, such as controller 102 that isprogrammed to apply the pulses and/or process feedback, as required. Itshould also be noted that a desired effect may be achieved by applyingvarious combinations of the pulses described below, in to differentsequences exemplars. The particular combinations of pulses that isappropriate for a particular patient may need to be determined on apatient by patient basis and may also change over time. Exemplary pulsesand sequences, however, are described below.

Exemplary Device

Pancreatic controller 102, includes generally a field source 104 forgenerating electric fields across pancreas 100 or portions thereof,which field source is controlled by control circuitry 106. A powersource 108 preferably powers field source 104 and control circuitry 106.The electrification is applied using a plurality of electrodes, forexample a common electrode 110 and a plurality of individual electrodes112. Alternatively other electrode schemes are used, for example aplurality of electrode pairs.

Electrical and other sensors may be provided as well, for input intocontroller 106. Although the electrodes may also serve as electricalsensors, in a preferred embodiment of the invention, separate sensors,such as a pancreatic sensor 114 or a glucose blood sensor 118 on a bloodvessel 120, are provided. Extra-cellular sensors, for measuringinter-cellular glucose levels, may also be provided. Controller 102 mayalso include an external unit 116, for example for transmitting power orprogramming to control circuitry 106 and/or power source 108.Alternatively or additionally, the external unit may be used to provideindications from a patient and/or sensor information. Alternatively oradditionally, the external unit may be used to provide alerts to thepatient, for example if the glucose level is not properly under control.Alternatively or additionally, such alerts may be provided from insidethe body, for example using low frequency sounds or by electricalstimulation of a nerve, a muscle or the intestines.

Additional details of this and other exemplary implementations will beprovided below. However, the general structure of controller 102 mayutilize elements and design principles used for otherelectro-physiological controllers, for example as described in PCTpublications WO97/25098, WO 98/10831, WO98/10832 and U.S. patentapplication Ser. No. 09/260,769, the disclosures of which areincorporated herein by reference. It is noted, however, that thefrequencies, power levels and duration of pulses in the pancreas may bedifferent from those used, for example, in the heart. In particular, thepower levels may be lower. Additionally, the immediate effects of anerror in applying a pulse to the pancreas are not expected to be as lifethreatening as a similar error in the heart would be, excepting thepossibility of tissue damage, which would cause an increase in severityof disease of the patient.

Tissue to which the Controller is Applied

The present invention is described mainly with reference to pancreatictissues. Such tissue may be in the pancreas or be part of an implant,possibly elsewhere in the body, or even in the controller envelopeitself, the implant comprising, for example, homologous, autologus orhetrologus tissue. Alternatively or additionally, the implant may begenetically modified to produce insulin.

Electrical Activity in the Pancreas

FIG. 2 is a diagram of an exemplary electrical activity of a single betacell, operating at slightly elevated glucose levels. In a large scalegraph 130, the activity of a single cell is shown as comprising aplurality of burst periods 132 comprising a plurality of individualaction potentials and separated by a plurality of interval periods 134,in which periods there are substantially no action potentials. As shownin a blow-up graph 140, each burst comprises a plurality ofdepolarization events 142, each followed by a repolarization period 144.The level of intra cellular calcium increases during the burst 132 anddecreases during interval 134.

The beta cells of a pancreas are arranged in islets, each such isletacts as a single activation domain, in which, when the glucose levelsare high enough, a propagating action potential is to be found. Thus,the aggregate electrical activity of an islet is that of a repeatingaverage action potential, at a frequency, of for example, 1 Hz, whichgenerally depends on the propagation time of an action potential throughthe islet. During intervals 134, if enough of the beta cells share theinterval, the entire islet may be generally silent or contain onlysporadic depolarization events.

Insulin Secretion Increase

The secretion of insulin, as differentiated from the production ofinsulin, may be increased in several ways, in accordance with preferredembodiments of the invention. The following methods may be appliedtogether or separately. Also, these methods may be applied locally, toselected parts of the pancreas, or globally, to the pancreas as a whole.

In a first method, the duration of a burst 132 is increased, thusallowing more calcium to enter the beta cells. It is believed that thelevel of calcium in the cell is directly related to the amount ofinsulin released by the cell. One type of pulse which may be applied isa pacing pulse, which forces the cells in the islet to depolarize. Sucha pulse is preferably applied at the same frequency as individual actionpotentials, e.g., 10 Hz. However, it may not be necessary to pace everyaction potential, a periodic pacing signal may be sufficient to forcecontinuous depolarization events. As well known in the art of cardiacpacing, many techniques can be applied to increase the captureprobability of the pacing signal, for example, double pacing, pulseshape and duration. These methods may also be applied, with suitablemodifications, to the pacing of the pancreas. An alternative method ofincreasing burst length is by increasing the sensitivity of the betacells to depolarization, for example, by sub-threshold pulses. Anothermethod of sensitizing the cells and/or increasing their action potentialduration is by hyperpolarizing the cells prior to a forced or normaldepolarization. Possibly, by preventing the normal reduction indepolarization frequency towards the end of a burst, a higher insulinoutput can be achieved for a same length burst.

In another method of increasing insulin secretion is by increasing thecalcium inflow efficiency of the individual action potentials. In apreferred embodiment of the invention, this is achieved by increasingthe length of the plateau durations 144, for example by applying anelectric pulse during the repolarization period associated with each ofdepolarization events 142. If such a pulse is applied early enough inthe repolarization phase of an action potential, period, prior toclosing of the calcium channels that provide the calcium inflow, thesechannels may stay open longer and will provide more calcium inflow. Itis noted that the frequency of firing of the beta cells may be reduced.

In some cells, the calcium inflow may be more efficient during thedepolarization period. In these cells, depolarization period 142 ispreferably extended, for example by applying an additional depolarizingpulse during the depolarization or very shortly after. Alternatively oradditionally, a pharmaceutical that enhances repolarization may beprovided, so that the repolarization time is shorter and more of theduration of a burst 132 can be spent in depolarization events.Alternatively or additionally, a plateau duration can be shortened byapplying a suitable pulse during the plateau. In one example, applying apulse after the calcium channels close, is expected to shorten therepolarization time. Alternatively or additionally, the individualaction potentials are paced, at a rate higher than normal for theglucose level. This pacing can override the end of repolarization andforce more frequent depolarization events. It is noted that aconsiderably higher pacing rate can be achieved by pacing than wouldnaturally occur for same physiological conditions. Possibly, the pacingrate is higher than physiologically normal for an islet at any glucoselevel.

In another method, the insulin secretion is enhanced by pacing theislets to have a higher frequency of bursts (as opposed to a higherfrequency of action potentials, described above). The resultingshortening in intervals 134 may have undesirable effects, for example bymaintaining high calcium levels in a cell for too long a period of time.In a preferred embodiment of the invention, this potential shortcomingis overcome by increasing the interval durations, for example, byapplying a hyper-polarizing pulse during the interval, thus allowingcalcium to leak out of the beta cells. It is noted however, that in somecases, sustained elevated calcium levels may be desirable. In whichcase, the intervals may be artificially shortened. In compensation, theeffectiveness of the burst in causing the secretion of insulin may bereduced.

A potential advantage of pacing is that the pacing signal will causedepolarization and associated recruitment of beta cells that would nototherwise take part in the activity of the pancreas. It is expected thatas intra-cellular calcium levels rise (or some other control mechanism),some cells will cease to participate in electrical activity. By applyinga pacing pulse, such cells are expected to be forced to participate and,thus, continue to secret insulin.

Another potential advantage of pacing is related to the synchronizationproblem. As can be appreciated, some types of controlling pulses need tobe applied at a certain phase in the cellular action potential. In apropagating action potential situation, it may be difficult to provide asingle pulse with timing that matches all the cells, especially as thedepolarization frequency increases. However, by forcing simultaneousdepolarization of an entire islet, the phases are synchronized, making adesirable pulse timing easier to achieve. It is noted, however, thateven if there is no pacing, some pulses, such as for extending a plateauof an action potentials, can be applied at a time that is effective fora large fraction of the cells in the islet.

Alternatively or additionally to calcium mediated vesicle transport, ina preferred embodiment of the invention, the electrical field alsodirectly releases insulin from the REP of the cell and/or from otherorganelles in the cell.

Insulin Secretion Suppression

In some cases, for example if the glucose level is too low, suppressionof insulin secretion may be desirable. Again, the following methods maybe applied together or separately. Also, as noted above, differentmethods may be applied to different parts of the pancreas, for example,by differently electrifying electrodes 112 of FIG. 1, thus for example,increasing secretion from one part of the pancreas while decreasingsecretion from a different part at the same time.

In a first method of insulin secretion reduction, the beta cells arehyper polarized, for example by applying a DC pulse. Thus, the cellswill not respond to elevated glucose levels by depolarization andinsulin secretion. It is noted that the applied pulse does not need tobe synchronized to the electrical activity. It is expected that thehyper polarization will last a short while after the pulse isterminated. Possibly, only the length of the interval is increased,instead of completely stopping the burst activity.

In a second method, the insulin stores of the pancreas are dumped, sothat at later times, the cells will not have significant amounts ofinsulin available for secretion. Such dumping may be performed forexample, with simultaneous provision of glucose or an insulinantagonist, to prevent adverse effects. The insulin antagonist, glucoseor other pharmaceuticals described herein may be provided in many ways.However, in a preferred embodiment of the invention, they are providedby external unit 116 or by an internal pump (not shown) in controller102.

In a third method, the plateau durations 144 are shortened, for exampleby over-pacing the islet cells, so that there is less available time forcalcium inflow. Alternatively, the intra-depolarization periods may beextended, by hyper-polarizing the cells during repolarization and afterthe calcium channels close (or forcing them closed by the hyperpolarization). This hyper polarization will delay the onset of the nextdepolarization and thus, reduce the total inflow of calcium over aperiod of time.

Alternatively or additionally, a hyper-polarizing pulse may be appliedduring a burst, to shorten the burst.

Affecting Insulin Production

Various feedback mechanisms are believed to link the electrical activityof the beta cells and the production of insulin. In a preferredembodiment of the invention, these feedback mechanisms are manipulatedto increase or decrease insulin production, alternatively oradditionally to directly controlling insulin secretion.

In a preferred embodiment of the invention, beta cells are preventedfrom secreting insulin, for example, by applying a hyper-polarizingpulse. Thus, the intra-cellular stores remain full and less insulin ismanufactured (and thus less insulin can reach the blood stream).

In a preferred embodiment of the invention, the beta cells arestimulated to release insulin. Depending on the cell, it is expectedthat if a cell is over stimulated, it is tired out and requires asignificant amount of time to recover, during which time it does notproduce insulin. If a cell is under stimulated, it is expected that itwill, over time produce less insulin, as it adapts to its newconditions. If a cell is stimulated enough, it will continuously produceinsulin at a maximal rate.

Pancreatic Response Control

In a preferred embodiment of the invention, rather than directly controlinsulin secretion levels, the response parameters of the pancreas aremodified, to respond differently to glucose levels. One parameter thatmay be varied is the response time. Another parameter is the gain(amplitude) of the response. In some situations, these two parameterscannot be separated. However, it is noted that by providing completecontrol of the pancreas, many different response profiles can beprovided by controller 102 directly.

In a preferred embodiment of the invention, the response time of thepancreas is increased or reduced by blocking or priming thefast-responding portions of the pancreas, in patients that have bothfast and slow responding portions. Blocking may be achieved, forexample, by partial or complete hyper-polarization. Priming may beachieved, for example, by applying a sub-threshold pulse, for example,just before depolarization. A potential advantage of such asub-threshold pulse is that it may use less power than other pulses.

The gain of the response may be controlled, for example, by blocking orby priming parts of the pancreas, to control the total amount ofpancreatic tissue taking part in the response. It is noted that priming“slow response” cells causes them to act as fast response cells, therebyincreasing the gain of the fast response. In some cases, the primingand/or blocking may need to be repeated periodically, to maintain thesensitivity profile of the pancreas as described.

Alternatively or additionally, the sensitivity of the pancreas may beenhanced (or decreased) by supporting (or preventing) the propagation ofaction potentials, for example by providing a suitable pharmaceutical.Octonal and Heptonal are examples of pharmaceuticals that decouple gapjunctions.

Exemplary Control Logic

FIG. 3 is a flowchart of an exemplary control logic scheme 200, inaccordance with a preferred embodiment of the invention. In this scheme,the intensity of pancreatic activity (and associated dangers) isincreased with the increase in glucose level. The various methods ofincreasing and decreasing pancreatic activity are described in moredetail above or below. Alerts are preferably provided to the patient atextreme glucose levels. In addition, the method prefers to error on theside of causing hyperglycemia, whose adverse effects are less criticalthan those of hypoglycemia, whose adverse effects are immediate. It isnoted than automated control logic for controlling glucose levels havebeen developed previously for insulin pumps and may also be applied forcontroller 102. An added ability of controller 102 is to suppress thebody's own production of insulin. An added limitation which controller102 preferably takes into account is the avoidance of damaging thepancreas by over stimulation.

In a step 202, the glucose level is determined. Many methods may be usedto determine glucose level. In a preferred embodiment of the invention,in cases of hyperglycemia, the measurement is repeated several timesbefore starting treatment. In cases of hypoglycemia, the measurementsmay be repeated few times or not at all, before starting treatment. Thecycle of treatment is preferably repeated every two to five minutes.Alternatively, in critical situations such as hypoglycemia, the cycle isrepeated even more frequently.

If the glucose level is under 60 (mg/dl) (step 204), further insulinproduction is preferably suppressed (206) and, optionally, the patientis alerted (208).

If the glucose level is between 60 and 150 (210), no action is taken, asthese are normal glucose levels.

If the glucose level is between 150 and 200 (212), the action takendepends on the previous action taken and the previous measured glucoselevel. If, for example the previous level was higher, the insulinsecretion activity may be maintained or reduced. If, on the other handthe glucose level was lower, the insulin secretion level may beincreased. For example, a pulse application ratio of 1:3 between burstthat are modified and bursts that are not modified may be provided ifthe glucose level is now reduced from its previous measurement. Itshould be appreciated, of course that the exact glucose levels and pulseparameters used for a particular patent will dependent only on thepatient's medical history, but also on that patient's particularresponse to the pulse parameters used. Some patients may not responds aswell as other patients and a more powerful pancreatic activitymodification schedule used.

If the glucose level is between 200 and 250 (216), the action taken(218) can depend on the previous action taken for example providing apulse application ratio between 1:1 and 1:2. Alternatively oradditionally, the action taken can depend on the degree of change,direction of change and/or rate of change of glucose levels. Preferably,a model of insulin secretion, digestion and/or effect on blood glucoselevel are used to assess the significance of changes in glucose level.

If the glucose level is between 250 and 300 (220), an even higher pulseapplication rate, such as 1:1, can be applied (222).

Glucose levels higher than 300 can be quite dangerous. Thus, if suchhigh rates are determined, a faster pacing rate, to the burst or to theindividual action potentials (224), may be applied. Alternatively oradditionally, a non-excitatory pulse to enhance secretion is alsoapplied to at least some of the pacing pulses.

If the level is over 400 (226), a bi-phasic pacing pulse for theindividual action potentials (228) may be provided. Such a pulse isexpected at its first phase to induce depolarization and at its secondphase to extend a plateau duration such that calcium inflow isincreased. Alternatively or additionally, if not previous applied,control of multiple pancreatic regions may be provided, to increase thetotal portion of the pancreas being used to secret insulin at a higherrate.

If the glucose level is over 500 (230) emergency measures may berequired, for example alerting the patient or his physician (232) anddumping all available insulin in the pancreas (234). A store ofavailable insulin may be maintained in the pancreas or in device 102 (oran associated insulin pump) for just these cases.

It should be noted the above method is only exemplary. For example, theexact action at each may be modified, as can be the mixture of actions,the pulse parameters and the delays before changing action.

This control method utilizes delayed closed loop control circuits.Alternatively, open-loop circuits, which are similar to conventionalglucose level management, may be provided. In such a loop, the amount ofinsulin output from a particular pulse application is known and isapplied responsive to an infrequent measurement of the glucose level,for example using a blood test. Periodic glucose level testing may beapplied to detect failed control. Intermediate control loops, controlcircuits having a smaller delay and combined control loops (having bothopen loop and closed loop) may be used in other preferred embodiments ofthe invention.

Long Term and Short Term Considerations

When applying electrification pulses in accordance with preferredembodiments of the invention, both short term and long term effects arepreferably taken into considerations. Short term effects, include, forexample effects on of insulin secretion and production. Long termeffects include, for example, effects on tissue viability and capabilityand electrode polarization.

As will be described below, long terms effects may be negative, such ascell death, or positive, such as training or promoting healing.

Polarization and encrustation of the electrodes are preferably avoidedby using ionic electrodes and applying balanced pulses (withsubstantially equal positive and negative charges). Alternatively,special coated electrodes, such as those coated with Iridium oxide ortitanium nitride, may be used. Alternatively or additionally, relativelylarge electrodes may be used. The balancing may be on a per pulse basisor may be spread over several pulses.

In a preferred embodiment of the invention, controller 102 stores in amemory associated therewith (not shown) a recording of the glucoselevels, the applied electrical and/or pharmaceutical control, foodintake and/or the effect of the applied control on electrical activityof the pancreas and/or effects on the blood glucose level.

Cellular Training

In a preferred embodiment of the invention, the applied electrificationand/or pharmaceutical profiles are used to modify the behavior of isletcells, in essence, training the cells to adapt to certain conditions. Itis expected that slightly stressing a beta cell will cause the cell tocompensate, for example by enlarging or by causing new beta cells to beproduced. Such regeneration mechanism are known to exist, for example asdescribed in “Amelioration of Diabetes Mellitus in partiallyDepancreatized Rats by poly(ADP-ribose) synthetase inhibitors. Evidenceof Islet B-cell Regeneration”, by Y Yonemura et. al, in Diabetes;33(4):401–404, April 1984, the disclosure of which is incorporatedherein by reference. Over stressing can kill the cell. Thus, the levelof stress that enhances the cells' operation may need to be determinedby trail and error for each patient. In a preferred embodiment of theinvention, the trial and errors are performed on different parts of thepancreas, preferably with a bias to under-stressing rather than for overstressing. In a preferred embodiment of the invention, over stressing isdetermined by a marked reduction in insulin output or by reduced orabnormal electrical response.

Alternatively or additionally, a cell insensitive to medium glucoselevels may be trained to be sensitive to lower glucose level, byexciting it more frequently and/or exciting it at times of slightlyelevated glucose levels.

In a preferred embodiment of the invention, such training pulses areapplied in combination with pharmaceuticals aimed to cause regenerationor healing.

It is noted that training and activation profile matching can also beused to maintain a cell in shape in a patient temporarily takinginsulin, or to support a cell that is recuperating, for example from atoxic material or from the onset of diabetes.

Pulse Shapes and Parameters

The range of pulse forms that may be applied usefully is very wide. Itmust be noted that the response of the cells in different patients or ofdifferent cells in a same patient, even to same pulses, is expected todiffer considerably, for example due to genetics and disease state.Also, the conduction of electrical signals in the vicinity of thepancreas is affected by the irregular geometrical form of the pancreasand the layers of fat surrounding it. These isolating layers may requirethe application of higher than expected amplitudes.

It is also noted that, at least for some embodiments, the application ofthe pulse is for affecting a certain portion of the pancreas and not theentire pancreas.

The lack of significant propagation of action potentials from one isletof the pancreas to another may require a relatively uniform field in thepart of the pancreas to be affected. However, completely uniform fieldsare not required as any edge effects are contained only to the isletswith the intermediate electric field strengths and/or because it isexpected that the cell behavior does not vary sharply with the appliedamplitude, except perhaps at certain threshold levels.

Further, the beta cells' behavior may be dependent on glucose level, oncellular insulin storage level and/or on previous activity of the cells.Unlike cardiac cells, which operate continuously and typically at alimit of their ability and/or oxygen usage, normal pancreatic cells areprovided with long rests and are operated at sub-maximal levels.

A first parameter of the pulse is whether it is AC or DC. As the pulsemay be applied periodically, the term DC pulse is used for a pulse thatdoes not alternate in amplitude considerably during a singleapplication, while an AC pulse does, for example having an intrinsicfrequency an order of magnitude greater that 1/pulse duration. In apreferred embodiment of the invention, DC pulses or pulses having asmall number of cycles per application, are used. In this usage, a pulsethat is synchronized to a burst is considered AC if it alternates inamplitude, for example ten times over the burst duration, even thoughthis frequency is actually lower than the action potential frequency.If, conversely, the pulse is a square pulse synchronized to theindividual action potentials, it will be considered a DC pulse, for thisdiscussion, although its actual frequency is higher than the AC pulse.

Exemplary frequencies for AC pulses applied to bursts are between 1 and1000 Hz and for AC pulses applied to action potentials, between 20 and2000 Hz. Preferably, the AC frequencies are between 50 and 150 Hz.

Various pulse durations may be used. An advantage of a DC long durationpulse is the lack of transients that might inadvertently affect othertissue. Such a pulse is expected to be useful for hyper-polarization ofcells and, thus, may last for several seconds or even minutes or hours.Preferably however, very long duration pulses are interrupted andpossibly, their polarity switched to prevent adverse effects such astissue polarization near the electrodes or over-polarization of thetarget tissue.

A pulse for affecting a burst may last, for example, between 1 ms and100 seconds. Exemplary durations are 10 ms, 100 ms and 0.5 seconds. Longpulses may be, for example 2 or 20 seconds long. A pulse for affecting asingle action potential will generally be considerably shorter, forexample being between 10 and 500 ms long. Exemplary durations are 20, 50and 100 ms. However, longer pulses, such as 600 or 6000 ms long may alsobe applied.

In AC pulses, various duty cycles can be used, for example 10%, 50%, 90%and 100%. The percentages may reflect the on/off time of the pulse orthey may reflect the relative charge densities during the on and offtimes. For example, a 50% duty cycle may be providing, on the average,50% of the maximum charge flow of the pulse.

A pulse may be unipolar or bipolar. In a preferred embodiment of theinvention, balanced pulses, having a total of zero charge transfer, areused. Alternatively, however, the balancing may also be achieved over atrain of pulses or over a longer period. It is expected that at leastfor some pulse effects, the islets will act independently of thepolarity of the applied pulse. However, changes in polarity may stillhave desirable effects, for example by creating ionic currents.

Different pulse envelopes are known to interact with cell membranes indifferent ways. The pulse envelope may be, for example, sinusoid,triangular, square, exponential decaying, bi-phasic or sigmoid. Thepulse may be symmetric or asymmetric. Optionally, the pulse envelope isselected to take into account variations in tissue impedance during thepulse application and/or efficiency and/or simplicity of the powerelectronics.

In a preferred embodiment of the invention, the pulse current iscontrolled, for example to remain within a range. Alternatively oradditionally, the pulse voltage is controlled, for example to remainwithin a range. Alternatively or additionally, both current and voltageare at least partly controlled, for example maintained in certainranges. Possibly, a pulse is defined by its total charge.

Different types of pulses will generally, but not necessarily, havedifferent amplitudes. The different effects of the pulse may also be afunction of the cell activity phase and especially the sensitivity ofthe cell to electric fields at the time of application. Exemplary pulseamplitude types are sub-threshold pulses that affect the depolarizationstate of the cell and channel affecting pulses. These pulses arenon-limiting examples of non-excitatory pulses, which do not cause apropagating action potential in the islet, either because of absolutelow amplitude or due to relative low amplitude (relative to cellsensitivity). An islet current of 5 pA is suggested in the Medtronic PCTpublication, for stimulating pulses.

Pacing pulses definitely cause a propagating action potential, unlessthe pacing pulse captures all the cells in the islet, in which casethere may be nowhere for the action potential to propagate to.

“Defibrillation” pulses are stronger than pacing pulses and cause a restin the electrical state of the affected cells.

Pore forming pulses, for example high voltage pulses, create pores inthe membrane of the affected cells, allowing calcium to leak in or outand/or allowing insulin to leak out.

The above pulse types were listed in order of increasing typicalamplitude. Exemplary amplitudes depend on many factors, as noted above.However, an exemplary pacing pulse is between 1 and 20 mA. An exemplarynon-excitatory pulse is between 1 and 7 mA. A sub-threshold pulse maybe, for example, between 0.1 and 0.5 mA. It is noted that the lack ofexcitation may be due to the timing of application of the pulse.

Simple pulse forms can be combined to form complex pulse shapes andespecially to form pulse trains. One example of a pulse train is adouble pacing pulse (two pulses separated by a 20 ms delay) to ensurecapture of a pacing signal.

Another example of a pulse train is a pacing pulse followed, at a shortdelay, by a plateau extending pulse and/or other action potentialcontrol pulses. Thus, not only is pacing forced, possibly at a higherthan normal rate, but also the effectiveness of each action potential isincreased. The delay between the pacing pulse and the action potentialcontrol pulse can depend, for example, in the shape of the actionpotential and especially on the timing of opening and closing of thedifferent ionic channels and pumps. Exemplary delays are 10, 50, 200 and400 ms.

Pulse Timings

Not only are various pulse forms contemplated, also different variationsin their periodicy are contemplated.

A first consideration is whether to synchronize an excitatory and/or anon-excitatory pulse to the pancreatic activity or not. If the pulse issynchronized, it can be synchronized to the activity of particular cellsor islets being measured. As noted above, a pacing pulse to the pancreascan force synchronization. The pulse may be synchronized to individualaction potentials and/or to burst activity. Within an action potential,the pulse can be synchronized to different features of the actionpotential, for example the depolarization, plateau, repolarization andquiescent period before depolarization. Not all action potentials willexhibit exactly these features.

Within a burst, a pulse may be synchronized to the start or end of theburst or to changes in the burst envelope, for example, significantreductions in the action potential frequency or amplitude.

As used herein, synchronization to an event includes being applied at adelay relative to the event occurring or at a delay to when the event isexpected to occur (positive or negative delay). Such a delay can beconstant or can vary, for example being dependent on the actionpotential or the burst activity.

The pulse may be applied at every event to which it is synchronized forexample every action potential or every burst. Alternatively, pulses areapplied to fewer than all events, for example at a ratio of 1:2, 1:3,1:10 or 1:20. An exemplary reason for reducing the pulse applicationratio is to prevent overstressing the beta cells and causing cellulardegeneration, or to provide finer control over secretion rate.

In some pulses, a significant parameter is the frequency of applicationof the pulse (as differentiated from the frequency of amplitudevariations in a single pulse). Exemplary frequencies range from 0.1 HZto 100 Hz, depending on the type of pulse.

In a preferred embodiment of the invention, the pulse parameters dependon the islet or cellular electrical and/or physiological state. Such astate may be determined, for example using suitable sensors or may beestimated from a global state of the glucose level.

Sensors

Many types of sensors may be usefully applied towards providing feedbackfor controller 102, including, for example:

-   -   (a) Glucose sensors, for example for determining the actual        glucose level and providing feedback on the effects of the        pancreatic treatment. Thus, for example, in a patient with        weakened pancreatic response, the pancreas will be stimulated to        secrete more insulin when the glucose levels are too high. Many        types of glucose sensors are known in the art and may be used        for the purposes of the present invention, including, for        example optical, chemical, ultrasonic, heart rate, biologic        (e.g., encapsulated beta cells) and electric (tracking beta cell        and/or islet electrical behavior). These sensors may be inside        the body or outside of it, connected to controller 102 by wired        or wireless means, be in contact with the blood or outside of        blood vessels.    -   (b) Digestion sensors, for example for detecting the        ingestion—or upcoming intake—of meals, and, for example,        prompting the production of insulin or increase in cell        sensitivity. Many suitable sensors are known in the art, for        example impedance sensors that measure the stomach impedance,        acceleration sensors that measure stomach or intestines        movements and electrical sensors that measure electrical        activity. Digestion sensing cells are inherently problematic if        they do not provide a measure of glucose actually ingested.        Preferably, they are used in combination with other sensors        and/or only if the digestion system is activated in a profile        matching eating, for example a long duration activation or        activation that advances along the digestive system. In a        preferred embodiment of the invention, stimulation during the        digestion may be stopped, to at least some parts of the pancreas        (e.g., ones comprising fewer islets), to avoid interfering with        other cell types in the pancreas, for example those that produce        digestive juices. Alternatively or additionally, the application        of stimulation in general may be optimized to reduce interaction        with non-beta cells, for example alpha cells. As alpha cells        generate glucagon, their stimulation may be determined by        tracking serum glucagon levels.    -   (c) Pancreatic activity sensors, for example electrodes coupled        to the entire pancreas, small parts of it, individual islet(s)        or individual cell(s) in an islet. Such sensors are useful not        only for providing feedback on the activity of the pancreas and        whether the applied pulses had a desired electrical (as opposed        to glucose-) effect, but also for synchronizing to the        pancreatic electrical activity.    -   (d) Calcium sensors, both for intracellular spaces and for        extra-cellular spaces. As can be appreciated, measuring calcium        inside a cell may affect the behavior of the cell. In a        preferred embodiment of the invention, only one or a few cells        are used as a sample for the state of the other cells. An        exemplary method of intracellular calcium measurement is to        stain the cell with a calcium sensitive dye and track its        optical characteristics. It is noted that both intra- and        extra-cellular calcium levels may affect the electrical and        secretary activity of beta cells.    -   (e) Insulin sensors, of any type known in the art may be used to        measure the response of a single islet, the pancreas as a whole        and/or to determine blood levels of insulin.

The measurements of the above sensors are preferably used to modify thepulse parameters or pulse application regime. Alternatively oradditionally, the sensors are used to track the response to the regimeand/or lack of application of pulses, or for calibration.

Different sensing regiments may be use, including continuous sensing,and periodic sensing. Some sensors may provide a frequent measurement,for example every few seconds or minutes. Other sensors may beconsiderably slower, for example taking a measurement every ten minutesor hour. If only a periodic measurement is required, the measurement maybe an average over the time between measurements or it may be an averageover a shorter time or an instantaneous value. In some cases a long termintegrative sensing, for example of total insulin production, isdesirable. A one-time chemical sensor may be suitable for suchintegrative sensing.

Types of Electrodes

The electrodes used may be single functionality electrodes, for exampleonly for pacing or only for non-excitatory pulses. Also, different typesof non-excitatory pulses, such as hyper-polarization and plateauextension pulses, may use different types of electrode geometries.Alternatively, a combination electrode, comprising both a pacing portionand a pulse application portion, may be provided. The different types ofelectrodes may have different shapes, for example due to the pacingelectrode being designed for efficiency and the pulse electrode beingdesigned for field uniformity. The two electrode functions may share asame lead or them may use different leads. Alternatively, a singleelectrode form is used for both pacing and non-excitatory pulseapplication.

FIGS. 4A–4D illustrate different types of electrodes that may besuitable for pancreatic electrification, in accordance with preferredembodiments of the invention.

FIG. 4A illustrates a point electrode 300 having a single electricalcontact area at a tip 304 of a lead 302 thereof.

FIG. 4B illustrates a line electrode 306 having a plurality of electriccontacts 310 along a length of a lead 308 thereof. An advantage of wireand point electrode is an expected ease in implantation using endoscopicand/or other minimally invasive techniques. In a preferred embodiment ofthe invention, multiple wire electrodes are implanted.

FIG. 4C illustrates a mesh electrode 312, including a lead 314 andhaving a plurality of contact points 318 at meeting points of mesh wires316. Alternatively or additionally, some of the wire segments betweenmeeting points provide elongate electrical contacts.

Each of the contact points can be made small, for example slightlylarger than an islet. Alternatively, larger contact areas are used. Inline electrodes, exemplary contact areas are 0.2, 0.5, 1, 2 or 5 mmlong. In some embodiments of the invention, smaller contact areas thanused for cardiac pacemakers may be suitable, as smaller fields may besufficient.

In some embodiments, volume excitation of the pancreas is desired. FIG.4D illustrates various volume excitation electrodes. A plate electrode320 includes a plate 322 that can simultaneously excite a large area. Aball electrode 324 includes a ball shaped contact area 326, with aradius of, for example, 2 or 4 mm, for exciting tissue surrounding ball326. A hollow volume electrode 328, for example, includes an open volumecontact area 330, for example a mesh ball or a goblet, which cane beused to excite tissue in contact with any part of ball 330, includingits interior. Another possibility is a coil electrode. Preferably, thecoils have a significant radius, such as 2 or 5 mm, so they enclosesignificant pancreatic tissue. It is noted that volume (and otherelectrodes as well) electrodes may encompass a small or large part ofthe pancreas or even be situated to electrify substantially all theinsulin producing parts of the pancreas.

Any of the above electrodes can be unipolar or bipolar. In bipolarembodiments, a single contact area may be spilt or the bi-polar activitymay be exhibited between adjacent contact points.

In addition, the above multi-contact point electrodes may have all thecontact points shorted together. Alternatively, at least some of thecontact points can be electrified separately and, preferably,independently, of other contact points in a same electrode.

Electrical contact between an electrode an the pancreas can be enhancedin many ways, for example using porous electrode, steroids (especiallyby using steroid eluting electrodes) and/or other techniques known inthe art. The type of electrode may be any of those known in the art andespecially those designed for long term electrical stimulation.

FIG. 4E illustrates a different type of electrode, in which a casing 332of controller 102 serves as one or multiple electrodes. Casing 332 maybe concave, convex or have a more complex geometry. Possibly, noexternal electrodes outside of casing 332 are used. Preferably, casing332 is then made concave, to receive the pancreas. Alternatively, atleast a common electrode 336 outside of controller 102 is provided.Alternatively or additionally, casing 332 of controller 102 serves as acommon electrode. In a preferred embodiment of the invention, aplurality of electrodes 334 are formed in casing 332. The electrodetypes can be any of those described above, for example. Preferably, butnot necessarily, electrodes 334 stick out of casing 332. In a preferredembodiment of the invention, controller 102 is placed in contact withpancreas 100, as an electrically insulating layer of fat usuallyencapsulates the pancreas. Preferably, the geometry of casing 332 ismade to conform to the shape of the pancreas, thus assuring contact withthe pancreas and minimal trauma to the pancreas by the implantation.Optionally, a flexible or multi-part hinged casing is provided, tobetter conform the casing to the pancreas.

The electrodes can be fixed to the pancreas in many means, including,for example, using one or more sutures or clips, providing coils orroughness in the electrode body, using adhesive or by impaling thepancreas or nearby tissue. An electrode may include a loop, a hole orother structure in it for fixing the suture or clip thereto. It is notedthat the pancreas does not move around as much as the heart, so lessresilient electrode and lead materials and attachment methods may beused.

Various combinations of the above electrodes may be used in a singledevice, for example a combination of a mesh electrode underneath thepancreas and a ground needle electrode above the pancreas. Such a groundelectrode may also be inserted in nearby structures, such as theabdominal muscles.

As described below, the pancreas may be controlled as plurality ofcontrolled regions. A single electrode may be shared between severalregions. Alternatively or additionally, a plurality of differentelectrodes may be provided for the different regions or even for asingle region.

Pancreatic Control Regions

FIG. 5 illustrates a pancreas subdivided into a plurality of controlregions 340, each region being electrified by a different electrode 342.Control regions 340 may overlap (as shown) or they may benone-overlapping. Possibly, the entire pancreas is also a controlregion, for example for insulin secretion suppression. Although asignificant percentage of the pancreas is preferably controlled, forexample 10%, 20%, 40% or 60%, part of the pancreas may remainuncontrolled, for example as a control region or as a safety measure.The number of control regions can vary, being for example, two, three,four, six or even ten or more.

One possible of different control regions is to allow one part of thepancreas to rest while another part is being stimulated to exert itself.Another possible use is for testing different treatment protocols ondifferent regions. Another possible use is to provide different controllogic for parts of the pancreas with different capabilities, to betterutilize those regions or to prevent damage to those reasons. Forexample, different pulses may be applied to fast responding or slowresponding portions. In addition, some parts of the pancreas may be morediseased than other parts.

Optionally, the density and/or size of the electrodes placement on thepancreas (And independently controllable parts of the electrodes) variesand is dependent, for example, on the distribution and density of isletcells in the pancreas. For example, a more densely populated section ofthe pancreas may be provided with finer electrical control. It is notedthat the distribution may be the original distribution or may be thedistribution after the pancreas is diseased and some of the cells diedor were damaged.

Implantation Method

The implantation of controller 102 can include implantation ofelectrodes and implantation of the controller itself. Preferably, thetwo implantations are performed as a single procedure. However, it isnoted that each implantation has its own characteristics. Implanting asmall casing into the stomach is a well-known technique and may beperformed, for example using a laproscope, using open surgery or usingkeyhole surgery.

Implantation of electrodes in the pancreas is not a standard procedure.Preferably, elongate, uncoiling or unfolding electrodes are used so thatelectrode implantation is simplified.

In a preferred embodiment of the invention, the electrodes are implantedusing a laproscopic or endoscopic procedure. Preferably, also controller102 is inserted using a laproscope or endoscope. In a preferredembodiment of the invention, the geometry of controller 102 is that of acylinder, so it better passes through an endoscope (flexible, relativelynarrow diameter tube) or a laproscope (rigid, relatively large diametertube). Alternatively, controller 102 is implanted separately from theelectrodes. In one example, the electrodes are implanted with aconnection part (e.g., wire ends) of the electrodes easily available. Asecond entry wound is made and the controller is attached to theconnection parts. Possibly, the electrodes are implanted connection partfirst. Alternatively, after the electrodes are implanted, the endoscopeis retracted, leaving the connection part in the body.

FIGS. 6A and 6B are flowcharts of implantation methods, in accordancewith preferred embodiments of the invention.

FIG. 6A is a flowchart 400 of a bile duct approach. First, an endoscopeis brought to a bile duct, for example through the stomach (402). Theendoscope then enters the bile duct (404) for example using methodsknown in the art. As shown, the endoscope may travel though the bileducts along the pancreas. Alternatively, the electrodes may be providedby a catheterization of the splenic artery or vein. Alternatively, theportal vein may be catheterized, for example via a laproscopic openingin the abdomen. The electrodes are implanted in, or alongside, thepancreas, for example in the blood vessels or the bile ducts, thepancreas being an elongated gland (406). In a preferred embodiment ofthe invention, the endoscope (or an extension thereof) is first advancedto the far end of the pancreas, the electrodes are attached to thepancreas and then the endoscope is retracted, leaving the electrodesbehind. Alternatively, the electrodes may be advanced out of thepancreas, by themselves or using a relative rigid and/or navigablejacket. Preferably, but not necessarily, imaging techniques, such aslight, ultrasound or x-ray imaging, are used to track the electrodeand/or the endoscope. The imaging may be from outside the body or frominside the body, for example from the tip of the endoscope.

Any damage to body structures is preferably repaired duringendoscope/catheter retraction (408). Alternatively, other arterialand/or venous techniques may be used. In some techniques, controller 102is implanted and then the electrodes are guided along or inside a bloodvessel or other body structure to the pancreas.

In bile duct implantation, a special coating may be provided on theelectrode or leads, to protect against the bile fluids. The contact partof the electrode may be embedded in tissue to prevent bile fluid damagethereto.

FIG. 6B is a flowchart 420 of an alternative implantation method. Anendoscope is advanced to the duodenum or other part of the intestinesadjacent the pancreas (422). Electrodes are extended from the intestinesinto the pancreas (424), while controller 102 remains in the intestines.The electrodes may also extend part way along the inside of theintestines. Electrodes on the far side of the pancreas may be implantedfrom a different part of the intestines or they pass through thepancreas. Alternatively, also the controller is pushed out through ahole formed in the side of the intestines. Alternatively, the controlleris enclosed in a pocket of the intestines, the pocket preferably formedby suturing or clipping together part of the intestines. Alternatively,the controller is attached to the intestines, for example using clips orusing sutures. Any damage to the intestines may then be repaired (426).

As noted above with reference to FIG. 1, controller 102 may be awireless device, with the control circuitry separate from theelectrodes. The electrodes can have individual power sources or they maybe powered (or recharged) using beamed power.

In an alternative embodiment, controller 102 is a multi part device, forexample comprising a plurality of mini-controllers, each mini controllercontrolling a different part of the pancreas. The activities of themini-controllers may be synchronized by communication between thecontrollers or by a master controller, for example in the separate,possibly external unit 116. Unit 116 may directly synchronize the minicontrollers and/or may provide programming to cause them to act in asynchronized manner. An exemplary geometry for a mini-controller is thatof two balls connected by a wire. Each ball is an electrode, one ballcontains a power source and the other ball contains control circuitry.Communication between the mini controllers may be, for example usingradio waves, preferably low frequency, or using ultrasound. Suitabletransmitter and/or receiver elements (not shown) are preferably providedin the mini-controllers.

Alternatively to an implanted controller, the controller may be externalto the body with the electrodes being inserted percutaneously to thepancreas, or even remaining on the out side of the body. Alternatively,the controller and the electrodes may be completely enclosed by theintestines. These “implantation” methods are preferred for temporary useof the device.

In some cases, proper implantation of sensors may be problematic, forexample sensors that impale single beta cells or islets. In an optionalprocedure, part of the pancreas is removed, sensors and/or electrodesare attached thereto and then the removed part is inserted back into thebody.

In the above embodiments, it was suggested to impale the pancreas usingelectrodes or electrode guides. In a preferred embodiment of theinvention, when impaling, care is taken to avoid major nerves and bloodvessels. In a preferred embodiment of the invention, the implantation ofelectrodes takes into account other nearby excitable tissue and avoidsinadvertent stimulation of such tissue.

Calibration and Programming

Pancreatic controller 102 may be implanted not only, after a stabledisease state is known, but also during an ongoing disease progression.Under these conditions and even in the steady state, cells that are tobe controlled by controller 102 are expected to be diseased and/orover-stressed and may behave somewhat unpredictably. Thus, in apreferred embodiment of the invention, optimizing the control of thepancreas may require calibrating the controller after it is implanted.However, it is noted that such calibration is not an essential featureof the invention and may even be superfluous, especially if a reasonableestimate of the pancreatic physiological state can be determined beforeimplantation.

FIG. 7 is a flowchart 500 of an exemplary method of controllerimplantation and programming, in accordance with a preferred embodimentof the invention. Other methods may also be practiced.

Before implantation, a patient is preferably diagnosed (502) and anexpected benefit of implantation is preferably determined. It is notedhowever, that controller 102 may also be used or diagnostic purposes,due to its ability to take measurements over extended periods of timeand determining the response of the pancreas cells to different stimuliand situations.

A controller is then implanted, for example as described above, and aninitial programming provided (504). The initial programming may beperformed while the controller is outside the body. However, In apreferred embodiment of the invention, the controller is capable ofextensive programming when inside the body, for example as describedbelow, to enable the controller to selectively apply one or more of themany different logic schemes and pulses, possibly differently to one ormore of the controlled areas.

During an information acquisition step (506) the behavior of thepancreas is tracked, possibly without any active control of thepancreas. This information acquisition preferably continues all throughthe life of the controller. In a preferred embodiment of the invention,the acquired information is periodically—and/or continuously—reported toa treating physician, for example using external unit 116. An exemplaryreport is the glucose levels in the body and the main events thataffected the glucose level.

Alternatively to mere information gathering, the information acquisitionalso uses test control sequences to determine the pancreatic response tovarious pulse forms and sequences.

In a preferred embodiment of the invention, the information acquisitionstep is used to determine physiological pathologies and especially todetect and feedback- and/or feedforward-mechanisms that are impaired.Such mechanisms are preferably supplemented, replaced and/or overriddenby controller 102.

In a preferred embodiment of the invention, various protocols are triedon small control regions to determine their effect.

The information acquisition, and later the calibration and programmingmay be performed on a per-person basis or even on a per-islet or perpancreatic portion basis. Preferably, a base line programming isdetermined from other patients with similar disorders.

Optionally, various test sequences are timed to match patient activitiessuch as eating, sleeping, exercising and insulin uptake. Also theprogramming of the controller may be adapted to a sleep schedule, mealtaking schedule or other known daily, weekly or otherwise periodicactivities.

After a better picture of how the pancreas is acting is formed, a firstreprogramming (508) may be performed. Such reprogramming may use anymeans known in the art such as magnetic fields and electromagneticwaves.

The reprogramming preferably implements partial control of the pancreas(510). Such partial control may be used to avoid overstressing theentire pancreas. Some of the controlled parts may be suppressed, forexample using hyper-polarizing pulses as described above. It is notedhowever, that since the pancreatic damage does not usually causeimmediate life threatening situations and because the pancreas is formedof a plurality of substantially independent portions, there isconsiderably more leeway in testing the effect of control sequences andeven the long term effects of such sequences, that there is in otherorgans such as the heart.

In an optional step 512, the interaction of pharmaceutical or hormonaltreatment with the controller may be determined. In this context is itnoted that cardiac and nerve electro-physiological pharmaceuticals maybe useful also for treatment of pancreatic disorders. Alternatively,pancreatic control may be desirable to offset negative side effects ofsuch pharmaceuticals taken for non-metabolic disorders.

Steps 508–512 may be repeated a plurality of times before settling downto a final programming 514. It is noted that even such final programmingmay be periodically reassessed (516) and then modified (518), forexample, as the pancreas and/or the rest of the patient improves ordegrades, or to apply various long-term effect control sequences.

In a preferred embodiment of the invention, a tissue viability testingof the controlled and or/uncontrolled parts of the pancreas ispreferably performed periodically, for example to assess patient state,to update the patient base line and to assess the efficiency of thetherapy. Exemplary methods of viability testing include analyzingelectrical activity, responses to changes in glucose level or insulinlevels and/or responses to various types of electrical stimulation.

In a preferred embodiment of the invention, the programming,measurements and/or prior attempted treatments (including possiblypharmaceutical treatments) are stored in a memory portion of controller102. Alternatively or additionally, the programming may include specialsequences that take into account taking of pharmaceuticals. In apreferred embodiment of the invention, when a patient takes apharmaceutical or insulin controller 102 is notified, for example bymanual input into external unit 116 or automatically by theadministration method. If the patient neglected to take thepharmaceutical, insulin, and/or glucose, a compensatory control sequenceis provided, possibly irrespective of whether an alert is provided tothe patient.

Experiment

In an exemplary experiment, a mesh unipolar electrode was placed under apig pancreas and a needle electrode was inserted into the overlyingabdominal wall as a ground. A pulsed current (5 Hz, 5 mA, 5 ms duration)was applied for five minutes and resulted in decrease in serum glucosefrom 89 to 74 mg/dl. Serum insulin increased from 3.8 to 5.37,microU/ml, measured using the ELISA method. Both glucose levels andinsulin levels returned to the baseline after 30 minutes, in a differentanimal, the application for 5 minutes of a pulse of 3 Hz, 12 mA and 5 msduration resulted in an insulin increase from 8.74 microU/ml to 10.858.74 microU/ml.

FIG. 8 is a chart showing the effect of such electrical stimulation oninsulin levels, in six animals.

Exemplary Applications

The above pancreatic controller 102 may be used after a diabetic stateis identified. Preferably however, the controller is used to betterdiagnose an evolving disease state and/or to prevent a final diabeticstate from ever occurring, for example by supporting the pancreas. Thus,a temporary device embodiment is preferably provided additionally topermanently implanted device.

In another application, strict control of body insulin output and bloodglucose levels is used not only to prevent obese patient from developingdiabetes by overworking of the pancreas, but also (simultaneously oralternatively) for reducing body weight. Such a scheme may requirestrict prevention of elevated glucose levels in blood, to avoid damageto the body. However, it is expected that by reducing insulin productionat “normal” glucose levels, feelings of hunger may be suppressed, aswell as reducing the increase in mass of adipose tissue.

In a preferred embodiment of the invention, controller 102 is a standalone device. However, a dual organ controller may be useful in somedisease states. In one example, it is noted that many patients withpancreatic disorders also have cardiac problems. Thus, a combinedcardiac/pancreatic controller may be provided, possibly sharing one ormore of a casing, programming means, power supply and control circuitry.In another example, a controller for the uterus and a pancreaticcontroller may be combined to protect against pregnancy related diabetesand improper uterine contractions.

Another exemplary dual organ controller is used for both the stomach andthe pancreas. Such a controller is useful for obese persons, to suppressstomach contractions and prevent feelings of hunger. At the same time,insulin level may be controlled to prevent hunger, or, in diabeticpatients, to prevent hyper- or hypo-glycemia.

It will be appreciated that the above described methods of controlling apancreas may be varied in many ways, including, changing the order ofsteps, which steps are performed more often and which less often, thearrangement of electrodes, the type and order of pulses applied and/orthe particular sequences and logic schemes used. Further, the locationof various elements may be switched, without exceeding the sprit of thedisclosure, for example, the location of the power source. In addition,a multiplicity of various features, both of method and of devices havebeen described. It should be appreciated that different features may becombined in different ways. In particular, not all the features shownabove in a particular embodiment are necessary in every similarpreferred embodiment of the invention. Further, combinations of theabove features are also considered to be within the scope of somepreferred embodiments of the invention. In addition, some of thefeatures of the invention described herein may be adapted for use withprior art devices, in accordance with other preferred embodiments of theinvention. The particular geometric forms used to illustrate theinvention should not be considered limiting the invention in itsbroadest aspect to only those forms, for example, where a ball electrodeis shown, in other embodiments an ellipsoid electrode. Although somelimitations are described only as method or apparatus limitations, thescope of the invention also includes apparatus programmed and/ordesigned to carry out the methods, for example using firmware orsoftware programming and methods for electrifying the apparatus to havethe apparatus's desired function.

Also within the scope of the invention are surgical kits which includesets of medical devices suitable for implanting a controller and such acontroller. Section headers are provided only to assist in navigatingthe application and should not be construed as necessarily limiting thecontents described in a certain section, to that section. Measurementsare provided to serve only as exemplary measurements for particularcases, the exact measurements applied will vary depending on theapplication. When used in the following claims, the terms “comprises”,“comprising”, “includes”, “including” or the like means “including butnot limited to”.

It will be appreciated by a person skilled in the art that the presentinvention is not limited by what has thus far been described. Rather,the scope of the present invention is limited only by the followingclaims.

1. A pancreatic controller, comprising: a glucose sensor, for sensing alevel of glucose or insulin in a body serum; at least one electrode, forelectrifying an insulin producing cell or group of cells; a power sourcefor electing said at least one electrode with a pulse that does notinitiate an action potential in said cell and has an effect ofincreasing insulin secretion; and a controller which receives the sensedlevel and controls said power source to electrify said at least oneelectrode to have a desired effect on said level.
 2. Apparatus accordingto claim 1, wherein said insulin producing cell is contiguous with apancreas and wherein said electrode is adapted for being placed adjacentsaid pancreas.
 3. Apparatus according to claim 1, wherein saidcontroller comprises a casing suitable for long term implantation insidethe body.
 4. Apparatus according to claim 1, wherein said electrode isadapted for long term contact with bile fluids.
 5. Apparatus accordingto claim 1, comprising an electrical activity sensor for sensingelectrical activity of said cell and wherein said power sourceelectrifies said electrode at a frequency higher than a senseddepolarization frequency of said cell, thereby causing said cell todepolarize at the higher frequency.
 6. Apparatus according to claim 1,wherein said pulse is designed to extend a plateau duration of an actionpotential of said cell, thereby allowing more calcium inflow into thecell.
 7. Apparatus according to claim 1, wherein said pulse is designedto reduce an action potential frequency of said cell, while not reducinginsulin secretion from said cell.
 8. Apparatus according to claim 1,wherein said pulse is designed to extend a duration of a burst activityof said cell.
 9. Apparatus according to claim 1, wherein said pulse hasan amplitude sufficient to recruit non-participating insulin secretingcells of said group of cells.
 10. Apparatus according to claim 1,comprising at least a second electrode adjacent for electrifying asecond cell or group of insulin secreting cells, wherein said controllerelectrifies said second electrode with a second pulse different fromsaid first electrode.
 11. Apparatus according to claim 10, wherein saidsecond pulse is designed to suppress insulin secretion.
 12. Apparatusaccording to claim 11, wherein said controller is programmed toelectrify said second electrode at a later time to forcefully secretesaid insulin whose secretion is suppressed earlier.
 13. Apparatusaccording to claim 11, wherein said second pulse is designed tohyper-polarize said second cells.
 14. Apparatus according to claim 1,wherein said controller electrifies said at least one electrode with apacing pulse having a sufficient amplitude to force a significantportion of said cells to depolarize, thus aligning the cells' actionpotentials with respect to the non-excitatory pulse electrification. 15.Apparatus according to claim 1, wherein said controller synchronizes theelectrification of said electrode to a burst activity of said cell. 16.Apparatus according to claim 1, wherein said controller synchronizes theelectrification of said electrode to an individual action potential ofsaid cell.
 17. Apparatus according to claim 1, wherein said controllerdoes not synchronize the electrification of said electrode to electricalactivity of said cell.
 18. Apparatus according to claim 1, wherein saidcontroller does not apply said pulse at every action potential of saidcell.
 19. Apparatus according to claim 1, wherein said controller doesnot apply said pulse at every burst activity of said cell.
 20. Apparatusaccording to claim 1, wherein said pulse has a duration of less than asingle action potential of said cell.
 21. Apparatus according to claim20, wherein said pulse has a duration of less than a plateau duration ofsaid cell.
 22. Apparatus according to claim 1, wherein said pulse has aduration of longer than a single action potential of said cell. 23.Apparatus according to claim 1, wherein said pulse has a duration oflonger than a burst activity duration of said cell.
 24. Apparatusaccording to claim 1, wherein said controller determines saidelectrification in response to a pharmaceutical treatment applied to thecell.
 25. Apparatus according to claim 24, wherein said pharmaceuticaltreatment comprises a pancreatic treatment.
 26. Apparatus according toclaim 24, wherein said controller applies said pulse to counteractadverse effects of said pharmaceutical treatment.
 27. Apparatusaccording to claim 24, wherein said controller applies said pulse tosynergistically interact with said pharmaceutical treatment. 28.Apparatus according to claim 24, wherein said controller applies saidpulse to counteract adverse effects of pacing stimulation of said cell.29. Apparatus according to claim 1, comprising an alert generator. 30.Apparatus according to claim 29, wherein said controller activates saidalert generator if said glucose level is below a threshold. 31.Apparatus according to claim 29, wherein said controller activates saidalert generator if said glucose level is above a threshold.
 32. A methodof controlling insulin secretion, comprising: providing an electrode toat least a part of a pancreas; applying a non-excitatory pulse to the atleast part of a pancreas, which pulse increases secretion of insulin.33. A method according to claim 32, comprising applying an excitatorypulse in association with said non-excitatory pulse.
 34. A methodaccording to claim 32, comprising applying a secretion reducingnon-excitatory in association with said non-excitatory pulse.
 35. Amethod according to claim 32, comprising applying a plurality of pulsesin a sequence designed to achieve a desired effect on said at least apart of a pancreas.
 36. A pancreatic controller, comprising: at leastone electrode, adapted for electrifying an insulin producing cell orgroup of cells; a power source for electrifying said at least oneelectrode with a waveform that does not initiate an action potential insaid cell and has an effect of increasing insulin secretion; and acontroller which controls said power source to have a desired effect ona blood glucose level.
 37. A controller according to claim 36, whereinsaid power source electrifies said at least one electrode with an ACwaveform.
 38. A pancreatic controller, comprising: a glucose sensor,adapted for sensing a level of glucose or insulin in a body serum; atleast one electrode, for electrifying an insulin producing cell or groupof cells; a power source for electrifying said at least one electrodewith a pulse that extends an action duration of a burst activity of saidcell; and a controller which receives the sensed level and controls saidpower source to electrify said at least one electrode to have a desiredeffect on said level.
 39. A method of controlling insulin secretion,comprising: providing an electrode adapted to electrify at least a partof a pancreas having an electrical activity; applying a non-excitatoryAC pulse to the at least part of a pancreas, not synchronized to saidelectrical activity, which pulse modifies an insulin response of saidpancreas to glucose levels.
 40. A method of controlling body glucoselevels, comprising: providing an electrode adapted to electrify at leasta part of a pancreas having an electrical activity; applying anon-excitatory AC pulse to the at least part of a pancreas, notsynchronized to said electrical activity, which pulse causes a reductionin glucose levels in a body containing said pancreas.